DESCRIPTION Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for cervical cancer. METHODS The USPSTF reviewed new evidence on the comparative test performance of liquid-based cytology and the benefits and harms of human papillomavirus (HPV) testing as a stand-alone test or in combination with cytology. In addition to the systematic evidence review, the USPSTF commissioned a decision analysis to help clarify the age at which to begin and end screening, the optimal interval for screening, and the relative benefits and harms of different strategies for screening (such as cytology and co-testing). RECOMMENDATIONS This recommendation statement applies to women who have a cervix, regardless of sexual history. This recommendation statement does not apply to women who have received a diagnosis of a high-grade precancerous cervical lesion or cervical cancer, women with in utero exposure to diethylstilbestrol, or women who are immunocompromised (such as those who are HIV positive).The USPSTF recommends screening for cervical cancer in women aged 21 to 65 years with cytology (Papanicolaou smear) every 3 years or, for women aged 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and HPV testing every 5 years. See the Clinical Considerations for discussion of cytology method, HPV testing, and screening interval (A recommendation).The USPSTF recommends against screening for cervical cancer in women younger than age 21 years (D recommendation).The USPSTF recommends against screening for cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. See the Clinical Considerations for discussion of adequacy of prior screening and risk factors (D recommendation).The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer (D recommendation).The USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years (D recommendation).
Abstract It is known that intestinal flora affects the number and function of NK cells through metabolites, thereby regulating the response of tumors to chemotherapy or immunotherapy. However, little is known about whether intratumoral bacteria are involved in NK cell-mediated antitumor immunity. In this study, 2bRAD-M analysis was performed on patient hepatocellular carcinoma and paired tissues to determine the composition of the intratumoral microbiota. Mass cytometry, flow cytometry, co-immunoprecipitation, immunoblotting, immunofluorescence, and DNA pull-down assays were used to evaluate the relationship between intratumoral bacteria, ferroptosis, and NK cell activity in Hu-SRC mice. Here, we found that the intratumoral B. parabrevis inhibited NK cell ferroptosis by promoting lipolysis into acetyl-CoA. Mechanistically, B. parabrevis catalyzed the acetylation of RORC, enhancing its binding to the NEDD4L promoter. NEDD4L induced ubiquitination of iron transporters SLC39A14, SLC39A8, and STEAP3. Functionally, B. parabrevis induced NK cells to differentiate into adaptability, cytotoxicity, and heat shock phenotypes, inhibiting the terminal phenotype and changing the tumor microenvironment from “cold” to “hot”. In conclusion, B. parabrevis enhanced the antitumor response of NK cells by regulating post-translational modifications. Our study identified a new strategy for utilizing intratumor bacteria for clinical treatment.
Abstract High-grade meningioma remains a therapeutic challenge. The first-line guideline drugs for high-grade meningioma are still lacking, highlighting the urgent need to uncover new therapeutic targets. As a cationic amino acid transporter, SLC7A1 was highly expressed in high-grade meningioma and associated with poor prognosis of patients. In this study, transcriptomic analyses at both the single-cell and bulk levels were employed to investigate the molecular function of SLC7A1. The Genomics of Drug Sensitivity in Cancer (GDSC) database was utilized for predicting potential drugs targeting high-SLC7A1 meningiomas. RNA sequencing was conducted to explore the differential activity of cancer hallmark pathways and transcription factors. The effects of SLC7A1 knockdown and drug treatment were validated in vitro and in vivo. Our results revealed that SLC7A1 regulates multiple signaling pathways involved in tumor proliferation, including E2F targets, G2M checkpoint, and MYC targets. Knockdown of SLC7A1 significantly inhibited the proliferation, invasion, and xenograft tumor growth of meningioma cells. Furthermore, SLC7A1-FOXM1/E2F4 regulatory axis may contribute to the malignant progression of meningioma. AZ628, predicted as a small molecule drug targeting high-SLC7A1 meningiomas, exhibited an excellent antitumor effect against meningioma in vitro, in vivo, and in organoid models. Additionally, AZ628 treatment also inhibited the transcriptional activity and protein expression of FOXM1 and E2F4, mirroring the effects of SLC7A1 knockdown in meningioma. In brief, our study demonstrated the tumor-promoting function of SLC7A1 by regulating the transcription factors FOXM1 and E2F4 in meningioma and identified SLC7A1 as a potential therapeutic target. Meanwhile, AZ628 is a promising small molecule drug for high-grade meningioma.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytology
Abstract How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell–T cell immunity hubs, where Ccr7 + Ido1 + dendritic cells, Cd160 + Cd8 + T cells, and Tnfrsf4 + Cd4 + T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9 + macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity.
Abstract SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.
Renáta Gáspár, Petra Diószegi, Dóra Nógrádi-Halmi
et al.
Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells.
Plant synaptotagmins (SYTs) are resident proteins of the endoplasmic reticulum (ER). They are characterized by an N-terminal transmembrane region and C2 domains at the C-terminus, which tether the ER to the plasma membrane (PM). In addition to their tethering role, SYTs contain a lipid-harboring SMP domain, essential for shuttling lipids between the ER and the PM. There is now abundant literature on Arabidopsis SYT1, the best-characterized family member, which link it to biotic and abiotic responses as well as to ER morphology. Here, we review the current knowledge of SYT members, focusing on their role in stress, and discuss how these roles can be related to their tethering and lipid transport functions. Finally, we contextualize this information about SYTs with their homologs, the yeast tricalbins and the mammalian extended synaptotagmins.
BACKGROUND: The dural fold between anterior and middle clinoid processes on mineralisation leads to the formation of caroticoclinoid foramen (CCF). Different morphology of this foramen presents with different clinical features. The present study reports the frequency of CCF in the population of Bihar, while providing an account of assimilated information from previous literature regarding the association of caroticoclinoid ligament ossification with age and human genetics. MATERIALS AND METHODS: The study was conducted on 100 adult dry human skulls of unknown age and sex, and 50 lateral view radiographs of the head. RESULTS: Of the 100 dry skull bones, 9 presented with different forms of CCF. Bilateral complete foramina were noticed in 2 (2%) skull bones, while the incomplete foramina were observed bilaterally in 3 (3%) and unilaterally in 4 (4%) skulls. The lateral view radiograph data (n = 50) presented with a bilateral foramen in one subject and unilateral complete CCF in two different subjects. On measurements of the diameters of the complete CCF the mean values observed were 4.06 mm and 4.51 mm on the right side, while that on the left side were 5.15 mm and 4.14 mm. For the incomplete foramina, the mean values for the vertical diameter were 4.48 mm on the right and 4.19 mm on the left side, respectively. CONCLUSIONS: The frequency of CCF in the present study population of Bihar was much lesser than that of previously studied populations. However, the variation in frequency of different morphological types of CCF was observed to be the same across populations. The variations in CCF’s metric data could help in predicting the morphological changes it causes to the clinoidal segment of the internal carotid artery, as well as in distinguishing its varieties.
The cyclin-dependent kinase 1 (Cdk1)–cyclin B (CycB) complex plays critical roles in cell-cycle regulation. Before <i>Drosophila</i> male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex of the nuclear pore complex. When this export is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls the cellular localization and activation of Cdk1. Cdk1–CycB continuously shuttled into and out of the nucleus before meiosis. Overexpression of CycB, but not that of CycB with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in <i>Nup62</i>-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in <i>Nup62-</i>silenced cells, whereas Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nuclei of <i>Nup62-</i>silenced cells, suggesting the involvement of another suppression mechanism. Silencing of <i>roughex</i> rescued Cdk1 inhibition and initiated meiosis. Nuclear export of Cdk1 ensured its escape from inhibition by a cyclin-dependent kinase inhibitor. The complex re-entered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1–CycB to initiate male meiosis.
Pulmonary airway sampling is always considered the chief diagnostic test for respiratory problems in dogs. The
trans tracheal wash (TTW) technique is commonly used for collecting airway aspirates for cytological analysis and bacteriological
examination. Tracheal lavage being the least invasive technique, requires local anesthesia or mild to moderate sedation and has
been found beneficial in dogs with pulmonary diseases including pneumonia, chronic bronchitis, eosinophilic bronchopneumopathy, neoplasia, etc. In the present study, TTW was performed on ten clinically healthy adult dogs weighing more than
10 kg, using a 14 gauge IV cannula and disposable dog catheter (4FG, OD 1.30 MM) replacing the costly designed catheter. The
study was performed with mild sedation using diazepam (0.5mg/kg) and ketamine (5mg/kg) combination intravenously in six
dogs and only local anesthesia in another four dogs. Transtracheal wash fluid revealed low cellularity with alveolar macrophages
as the predominant cell type, followed by respiratory epithelial cells, lymphocytes, eosinophils, and other cells (mast cells,
plasma cells, goblet cells, basophils). This article summarizes an indigenous cost-effective TTW procedure for obtaining a
representative cytological sample from the pulmonary airways.
Advancements in high–throughput microscopy imaging have transformed cell analytics, enabling functionally relevant, rapid, and in–depth bioanalytics with Artificial Intelligence (AI) as a powerful driving force in cell therapy (CT) manufacturing. High–content microscopy screening often suffers from systematic noise, such as uneven illumination or vignetting artifacts, which can result in false–negative findings in AI models. Traditionally, AI models have been expected to learn to deal with these artifacts, but success in an inductive framework depends on sufficient training examples. To address this challenge, we propose a two–fold approach: (1) reducing noise through an image decomposition and restoration technique called the Periodic Plus Smooth Wavelet transform (PPSW) and (2) developing an interpretable machine learning (ML) platform using tree–based Shapley Additive exPlanations (SHAP) to enhance end–user understanding. By correcting artifacts during pre–processing, we lower the inductive learning load on the AI and improve end–user acceptance through a more interpretable heuristic approach to problem solving. Using a dataset of human Mesenchymal Stem Cells (MSCs) cultured under diverse density and media environment conditions, we demonstrate supervised clustering with mean SHAP values, derived from the ‘DFT Modulus’ applied to the decomposition of bright–field images, in the trained tree–based ML model. Our innovative ML framework offers end-to-end interpretability, leading to improved precision in cell characterization during CT manufacturing.
Erden Eren, Jeannie-Marie Leoutsakos, Juan Troncoso
et al.
The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ<sub>42</sub>, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ<sub>42</sub> levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ<sub>42</sub>-laden NDEVs may be an adaptive mechanism in AD.
Takahiro Utsumi, Yohei Taniguchi, Yuri Noda
et al.
Abstract Thoracic SMARCA4‐deficient undifferentiated tumors are a new type of neoplasm that commonly occur in the mediastinum, progress rapidly, and show a poorer prognosis. We report a case of thoracic SMARCA4‐deficient undifferentiated tumor in the right thoracic cavity in a patient with a history of heavy smoking and presenting with respiratory distress and hemoptysis. Imaging showed pleural effusion and thickening. A diagnostic right pleural biopsy yielded multiple white nodules and pale bloody pleural effusion accumulated in the right thoracic cavity. Histopathologically, the tumor cells were large, some exhibited rhabdoid cytology, and they were surrounded by an infiltration of inflammatory cells. These tumor cells were negative for SMARCA4, p40, NUT, and claudin‐4, leading to establishing a diagnosis of thoracic SMARCA4‐deficient undifferentiated malignancy. We treated the patient with atezolizumab, carboplatin, and nab‐paclitaxel. The patient achieved stable disease at 7 months during this study. Although there is no standard treatment of this disease, our reported treatment may contribute to improved prognosis, requiring further research.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
The magnitude of eosinophil mobilization into respiratory tissues drives the severity of inflammation in several airway diseases. In classical models of leukocyte extravasation, surface integrins undergo conformational switches to high-affinity states via chemokine binding activation. Recently, we learned that eosinophil integrins possess mechanosensitive properties that detect fluid shear stress, which alone was sufficient to induce activation. This mechanical stimulus triggered intracellular calcium release and hallmark migration-associated cytoskeletal reorganization including flattening for increased cell–substratum contact area and pseudopodia formation. The present study utilized confocal fluorescence microscopy to investigate the effects of pharmacological inhibitors to calcium signaling and actin polymerization pathways on shear stress-induced migration in vitro. Morphological changes (cell elongation, membrane protrusions) succeeded the calcium flux in untreated eosinophils within 2 min, suggesting that calcium signaling was upstream of actin cytoskeleton rearrangement. The inhibition of ryanodine receptors and endomembrane Ca<sup>2+</sup>-ATPases corroborated this idea, indicated by a significant increase in time between the calcium spike and actin polymerization. The impact of the temporal link is evident as the capacity of treated eosinophils to move across fibronectin-coated surfaces was significantly hampered relative to untreated eosinophils. Furthermore, we determined that the nature of cellular motility in response to fluid shear stress was nondirectional.
Abstract Osteosarcoma is one of the most common primary malignancies in bones and is characterized by high metastatic rates. Circulating tumor cells (CTCs) derived from solid tumors can give rise to metastatic lesions, increasing the risk of death in patients with cancer. Here, we used bioinformatics tools to compare the gene expression between CTCs and metastatic lesions in osteosarcoma to identify novel molecular mechanisms underlying osteosarcoma metastasis. We identified TRAIP as a key differentially expressed gene with prognostic significance in osteosarcoma. We demonstrated that TRAIP regulated the proliferation and invasion of osteosarcoma cells. In addition, we found that TRAIP promoted KANK1 polyubiquitination and subsequent degradation, downregulating IGFBP3 and activating the AKT pathway in osteosarcoma cells. These results support the critical role of the TRAIP/KANK1/IGFBP3/AKT signaling axis in osteosarcoma progression and suggest that TRAIP may represent a promising therapeutic target for osteosarcoma.
Ana Jordan-Paiz, Sandra Franco, Miguel Angel Martinez
Synonymous codon pair deoptimization is an efficient strategy for virus attenuation; however, the underlying mechanism remains controversial. Here, we optimized and deoptimized the codon pair bias (CPB) of the human immunodeficiency virus type 1 (HIV-1) envelope (<i>env</i>) gene to investigate the influence of <i>env</i> synonymous CPB recoding on virus replication capacity, as well as the potential mechanism. We found that <i>env</i> CPB deoptimization did not always generate attenuation, whereas CPB optimization attenuated virus replication in MT-4 cells. Furthermore, virus attenuation correlated with reduced Env protein production but not with decreased viral RNA synthesis. Remarkably, in our model, increasing the number of CpG dinucleotides in the 5′ end of <i>env</i> did not reduce the replication capacity of HIV-1. These results indicate that factors other than CPB or CpG content may have impacted the viral fitness of the synonymously recoded study variants. Our findings provide evidence that CPB recoding-associated attenuation can affect translation efficiency. Moreover, we demonstrated that an increased number of CpGs in the 5′ end of HIV-1 <i>env</i> is not always associated with reduced virus replication capacity.
Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.